The aetiopathology of peptic ulcer disease is best understood in terms of an imbalance between mucosal defense factors (bicarbonate, mucin, prostaglandin, nitric oxide, some peptides and growth factors) and aggressive factors (acid, pepsin and H. pylori). Peptic ulcers do not occur when there is a balance between the aggressive factors and the defensive factors, but when the attacking factors become stronger than normal or when the defensive factors weaken, peptic ulcers can occur (Hoogerwerf and Pasricha, 2001).
Helicobacter pylori (H. pylori) is a ubiquitous, gram negative, highly motile, S-shaped, microaerophilic bacterium which colonizes the human gastric mucosa for extended time period. H. pylori infection is widespread with seroprevalence in the developed world between 30-60% (Everhart, 2000). Infection with the bacterium is usually contracted during childhood and patients remain infected for life unless treated. H. pylori infection has been shown to result in the development of chronic gastritis, gastro esophageal reflux disorder (GERD), and peptic ulcer diseases including gastric and duodenal ulcers. It is also linked to mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma (Go, 2000).
The other major etiology of peptic ulcer diseases is hyperacid secretion. For ulcers that are not caused by H. pylori, acid suppressive therapy alone with antisecretory agents is recommended in the form of H2-receptor antagonists or proton pump inhibitors, besides simple use of acid-neutralizing agents like antacids (Hoogerwerf and Pasricha, 2001). reflux
The eradication of the bacterium by triple therapies consisting of two antibiotics and a proton pump inhibitor in infected patients has resulted in good healing rates for both active gastritis and peptic ulcer diseases (Graham et. al., 1992). However, rising prevalence of acquired resistance of H. pylori to some antibiotics (Glupczynski et al., 2001), ulcer recurrence and the relatively high incidence of side effects (Wermeille et al., 2002) are the major causes for concern in recent times. Strains resistant to clarithromycin (CLR) and metronidazole (MNZ) have been well documented (Mégraud, 2004) while resistance to amoxicillin (AMX) and tetracycline was mainly reported in Asian countries (Wu et al., 2000, Kwon et al., 2000). On the other hand, as far as the use of antisecretory agents H2 receptor blockers and proton pump inhibitors are concerned, a number of side effects are reported. The adverse drug interaction of the cytochrome P450 system with H2-receptor blocker, hypersensitivity and damage of the liver by proton pump inhibitors, requirements of multiple doses of antacids to alleviate symptomatic-only relief, coupled with ulcer recurrence problems (Bullard, 1997) necessitate searching for better therapeutic management of hypersecretory disorders.
Regarding the treatment of H. pylori infection, reference may be made to an U.S. patent (Borody, 1993) which described a method consisting of the administration of a bismuth compound, an antibiotic belonging to the groups of penicillin and tetracycline, and a second antibiotic, such as metronidazole. The relevant therapy thus consists of the administration of three medications several times a day. There are other patents describing multiple therapies for the eradication of H. pylori, such as Neeman et al., 1995, 1996; Shell, 1996). None of these however eliminate the need to administer complex medications.
As antisecretory agents, several patents disclose the use of diverse molecular structures like fumagillol (Yanai et al. 1998), diphenyl ether phosphate esters (Catrenich et al., 1995), heterocyclyl-phenyl-(sulfonyl- or phosphonyl)-amidines (Cereda et al., 1987), N-alkylated benzo- and hetero-fused compounds (Schiehser et al., 1986), N-aryl-N′-(1,4,5,6-tetrahydropyrimidin-2-yl)ureas (Ramussen, 1984), 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine (Arcari et al., 1980), 1-(4-chlorophenyl)-3-(1-ureido)-2-imidazolidinone (Schwan et al., 1978), 1,3-dimethyl-1H-pyrazolo(4,3-d)pyrimidine-7(6H)-ones (Ratajczyk et al., 1976), 4-acetoxy-1,2,3,4-tetrahydro-2,2-dimethyl-6,7-methylenedioxy isoquinolinium iodide (Schwan et al., 1978), furan or thiophene derivatives of iminomethyl piperidine (Scott, 1986), and 0-(carboxymethyl)-4-chromanone oxime (Wright et al., 1978).
Flavonoids, a class of polyphenols compounds, are present in many fruits and vegetables and offer a large number of biological activities. The antimicrobial activity of different types of flavonoids, either isolated from different plants or their chemically modified analogues, have been reported (Cushnie and Lamb, 2005). Anti peptic ulcer activity including anti H. pylori activity of naturally occurring flavonoids have also been documented (Bell et al., 1995; Ohsaki et al., 1999; Fukai et al., 2002; Park et al., 2004).
Three U.S. patents have disclosed the use of flavone or flavanone compounds for preventing or treating damages to the mucosal lining of the gastrointestinal tract (Ares et al., 1995; Yoo et al., 0.2000; Xu, 2004) while a Chinese patent (CN1615947) has implicated the use of flavones for treating oral ulcer, gastric ulcer, burn, scald and traumatic infection. A recent patent application from our group has disclosed the use of flavonoids for the treatment of gastrointestinal toxicity, associated symptoms and ulcers (Rao et al., 2007).
A Japanese patent (JP11228407) and an U.S. patent (Higuchi et al., 2001) disclosed the use of flavones for increasing the activity of beta lactam antibiotics against methicillin-resistant Staphylococcus aureus. An U.S. patent disclosed the use of biflavonoids in treating viral infection (Lin et al., 2002), while another U.S. patent disclosed the use of 3-methylene flavanones and 3-methylene chromanones having activity against microorganisms (Buckler et al., 1980). The use of flavones as antibacterial agents exhibiting suppressing effect against indigenous dermatic bacteria has been disclosed in the patent JP62145017. The antibacterial activity of an antibiotic flavone has also been disclosed in an US patent (Richards et al., 1972). Use of chrysin as antibacterial, antiviral and immunostimulatory agents has been patented (Markonius, 1995, 1999). Use of oroxylin A as inducible nitric oxide synthase inhibitor, cyclooxygenase-2 inhibitor and potassium channel activator has also been patented (Lee et al., 2004).
In view of the efforts towards searching for flavonoids which could be active against antibiotic-resistant bacterial strains or which would not impart resistance to otherwise susceptible strains (Xu and Lee, 2001; Iinuma et al., 1994; Liu et al., 2001), the inventors were interested in designing, synthesizing and bioevaluating a series of chrysin and oroxylin A derivatives with a view to imparting both anti H. pylori as well as antisecretory property in the flavone core structure.